PROJECT SUMMARY This application focuses on utilization of environmental enrichment (EE) to attenuate the effects of perinatal hypoxia (HX) on the developing brain. Hypoxic damage to the brain is often sustained as a consequence of preterm birth, and results in cognitive and behavioral disabilities throughout childhood and beyond. This oxygenation failure predisposes preterm infants to white matter (WM) injury, resulting in the loss of oligodendrocyte (OL) glial cells and therefore myelination. One promising non-invasive therapy for promoting recovery after perinatal HX is EE - a combination of social and physical enhancement of surroundings that provides mammals with more complex social interactions, exposure to novel stimuli, and an opportunity for voluntary physical activity. Previous studies have demonstrated that the environment affects neural plasticity and functional recovery after brain injury, and that social, family, and environmental factors can improve cognitive outcome in premature children. This suggests that the environment can be used as a modulator of recovery in premature brain injury, and may enhance the endogenous repair of developing WM after HX insult to restore WM-dependent behavioral function. To test this hypothesis, the effects of EE on cellular, ultrastructural, and functional recovery after HX will be determined using a rodent model of perinatal HX. First, the critical neurodevelopmental window and individual components of EE required for OL recovery after HX will be defined. Then, using genetic manipulations in conditional loss of function mice, the role of EE-induced de novo myelination after HX will be determined. The proposed study utilizes a novel approach to enhance recovery from WM injury in the brain during critical periods of neurodevelopment, and importantly, will aid in the development of new therapeutic strategies to reduce the long-term neurologic sequelae of preterm birth.